The invention relates to the inhibition or prevention of inflammation and adhesion formation using pharmaceutical compositions containing hyaluronic acid, non-steroidal inflammatory drugs, and at least one organic salt of at least one divalent metal selected from the group consisting of magnesium acetate, zinc acetate, calcium gluconate, and ferrous gluconate.
During the normal healing process in response to tissue trauma, initial damage to the mesothelial layer evokes an inflammatory response which is mediated by activation of the kinin, complement and clotting systems (Stangel et al., J. Reprod. Med. 29:143, 1984). A serofibrinous exudate including kinin, prostaglandins, and histamine is produced, which increases the permeability of local blood vessels (Buckman et al., J. Surg. Res. 20:1, 1976; Stangel et al., supra). Leukocytes are attracted to the site by chemotaxis and the fibrinous exudate is attracted to the damaged tissue surface due to permeability factors. Fibrin is present in free blood as fibrinogen and it is also a normal product of the clotting cascade. During coagulation, thin strands of fibrinous adhesions form on the damaged surface within the first three hours (Stangel et al. supra). The majority of these fibrinous adhesions are lysed within the first 72 hours as part of the normal healing process and never represent any type of clinical complication for the individual.
In some cases, however, these initial fibrinous adhesions persist and become organized into permanent, thick, fibrous adhesions which represent a significant clinical problem across many different fields of medicine. This phenomenon is often associated with joint disease, accidental trauma, and surgical procedures, and is thought to be triggered by an adverse response to many common stimuli including, for example, an overwhelming inflammatory response, tissue ischemia, and the loss of natural physical tissue separation. For example, post-surgical peritoneal adhesions are one of the leading causes of intestinal blockage or obstruction (Ellis, Surg. Gynecol. Obstet. 133:497, 1971), and are also of great concern to surgeons who attempt to improve fertility in women through reconstruction. Pelvic adhesions can impair fertility by interfering with the ability of the fallopian tubes to pick up the ovum (Holtz, Fertil. Steril. 41:497, 1984; Diamond and Hershlag, Prg. Clin. Biol. Res. 358:23, 1990). The formation of permanent adhesions in tendons and joints is a major cause of decreased mobility and chronic pain.
Most research on adhesion prevention agents pertains to post-surgical abdominal adhesion, and minor efforts have been directed to other adhesions such as those experienced in the thorax and tendons. Some of these studies focused on the prevention of fibrin deposition as a strategy to prevent post-surgical adhesion. These strategies included the use of anticoagulants (Holtz, Prog. Clin. Biol. Res. 381:81, 1993); and irrigation (Tulandi, Prog. Clin. Biol. Res. 381:149, 1993); and the separation of tissue surfaces using (a) dextran lavage of intraperitoneal procedures (diZerega, Prog. Clin. Biol. Res. 381:1, 1993); (b) oxidized cellulose films, e.g., Interceed (diZerega, supra); (c) carboxymethyl cellulose solution (Elkins et al., Fertil. Steril. 41:929, 1984); (d) chondroitin sulfate solutions (Oelsner, J. Reprod. Med. 32:812, 1987); (e) polyvinyl pyrrolidine solutions (Goldberg et al., Arch. Surg. 115:776, 1980); (f) Polyoxamer 407 solutions (Steinleitner et al., Obstet. Gynecol. 77:48, 1991); and (g) Gortex films (Boyers et al., Prog. Clin. Biol. Res. 358:93, 1990).
Other approaches to prevent post-surgical adhesions have relied on the (a) removal of fibrin matrix through the use of fibrinolytics and proteolytic enzymes (Kapur et al., Arch. Surg. 105:761, 1972; Stangel et al. 1984, supra) or tissue-type plasminogen activator (Evans, Am. J. Surg. 165:229, 1993); and (b) surgical removal of adhesions (Stangel et al. 1984, supra).
Still other strategies have focused on inhibiting the overwhelming inflammatory response to injury which has been found to be one of the key factors in adhesion formation. A variety of pharmacological agents which have anti-inflammatory properties, including corticosteroid, antihistamines, antiprostaglandins, and non-steroidal anti-inflammatory agents have been investigated in terms of their potential as anti-adhesion agents. Of those agents studied, non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to be among the most successful in inhibiting inflammation and adhesions formation (diZerega, Prog. Clin. Biol. Res. 381:1, 1993). However, early clinical studies were not as encouraging as expected, based on earlier animal studies. One of the main concerns in administering NSAIDs is the method of delivery. Systemic delivery of the drugs requires sufficient blood supply to the injured site; however, this is often disrupted during surgery. Thus, tissue ischemia not only stimulates adhesion formation it also prevents the effective systematic delivery of NSAIDs (diZerega, 1993 supra). Continuous delivery of the NSAID, tolmetin sodium, was reported to be highly effective in preventing peritoneal adhesions (Rodgers et al., Int. J. Fertil. 35:40, 1990). However, continuous drug delivery is impractical in a clinical setting. Therefore, there is a distinct need for appropriate and effective, non-toxic local delivery systems for non-steroidal anti-inflammatory drugs.
Another approach to adhesion prevention which has met with a certain degree of success entails the use of hyaluronic acid. Hyaluronic acid has been tested in several different model systems to determine its efficacy in preventing adhesion formation and reformation. There is extensive literature on the use of HA solutions to reduce postoperative adhesion formation following abdominal and orthopedic surgery. Although the results of various studies have been somewhat contradictory, there appears to be a consensus that to achieve significant biological efficacy, HA compositions must be of high viscosity, high HA concentration, and must contain high molecular weight and highly conformationally ordered HA molecules (Balazs, U.S. Pat. No. 4,141,973). However, these properties limit the practical use of such HA solutions, especially in methods requiring injection of the compositions into small spaces (e.g., tendon sheaths, joints) because, generally, solutions containing high concentrations of HA having a molecular weight greater than 8.times.10.sup.5 Daltons are not suitable for use as injectable formulations.
In a recent study, Abe et al. (J. Surg. Res. 55:451, 1990) evaluated the efficacy of sodium tolmetin in a medium of hyaluronic acid and phosphate buffered saline (PBS) in the standard adhesion model involving the injury of abrasion and devascularization of both uterine horns of rabbits. Their treatment consisted of 15 ml of hyaluronic acid (2.5%, 8000 CPS) and tolmetin sodium (1 mg/ml) in PBS, administered intra-peritoneally via a syringe. Gross observations indicate that the occurrence of mild to severe adhesions within 72-96 hours after surgery occurred in 25% of those animals treated with HA-tolmetin sodium, whereas mild to severe adhesions were observed in 60% of untreated controls during the same time period.
In summary, developing appropriate and effective therapies for inhibiting inflammation and adhesion formation is still a major challenge. While NSAIDs have been shown to decrease the tissue inflammatory response and enhance fibrinolytic potential in peritoneal tissues previous studies have shown that these drugs need to be delivered to specifically targeted areas for several days to be effective. In turn, while hyaluronic acid has demonstrated potential as a drug carrier, the concentrations and molecular weights required for biological efficacy prohibit the practical use of this compound in an injectable form. Therefore, more effective strategies for the treatment of tissue trauma associated with adhesion formation are still needed.